Changes of renal AQP2, ENaC, and NHE3 in experimentally induced heart failure: response to angiotensin II AT₁receptor blockade

Abstract

Lü tken SC, Kim SW, Jonassen T, Marples D, Knepper MA, Kwon TH, Frøkiaer J, Nielsen S. Changes of renal AQP2, ENaC, and NHE3 in experimentally induced heart failure: response to angiotensin II AT 1 receptor blockade. Am J Physiol Renal Physiol 297: F1678 -F1688, 2009. First published September 23, 2009 doi:10.1152/ajprenal.00010.2009.-Heart failure (HF) was induced by ligation of the left anterior descending artery (LAD). Left ventricular end-diastolic pressure (LVEDP) Ͼ25 mmHg (at day 23 after LAD ligation) was the inclusion criterion. The rats were divided into three groups: sham-operated (Sham, n ϭ 23, LVEDP: 5.6 Ϯ 0.6 mmHg), HF (n ϭ 14, LVEDP: 29.4 Ϯ 1.4 mmHg), and candesartan (1 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 sc)-treated HF (HF ϩ Can, n ϭ 9, LVEDP: 29.2 Ϯ 1.2 mmHg). After 7 days (i.e., 29 days after LAD ligation) semiquantitative immunoblotting revealed increased abundance of inner medulla aquaporin-2 (AQP2) and AQP2 phosphorylated at Ser 256 (p-AQP2) in HF. There was also markedly enhanced apical targeting of AQP2 and p-AQP2 in inner medullary collecting duct (IMCD) in HF compared with Sham rats, shown by immunocytochemistry. Candesartan treatment significantly reversed the increases in both AQP2 and p-AQP2 expression and targeting. In contrast, there were only modest changes in other collecting duct segments. Semiquantitative immunoblots revealed increased expression of type 3 Na ϩ /H ϩ exchanger (NHE3) and NaϪ cotransporter (NKCC2) in kidneys from HF compared with Sham rats: both effects were reversed or prevented by candesartan treatment. The protein abundance of ␣-epithelial sodium channel (␣-ENaC) was increased while ␤-ENaC and ␥-ENaC expression was decreased in the cortex and outer stripe of the outer medulla in HF compared with Sham rats, which was partially reversed by candesartan treatment. These findings strongly support an important role of angiotensin II in the pathophysiology of renal water and sodium retention associated with HF. collecting duct; aquaporin; type 3 Na ϩ /H ϩ exchanger; Na ϩ -K ϩ -2Cl Ϫ cotransporter; epithelial sodium channel ACUTE MYOCARDIAL INFARCTION is a common cause of heart failure (HF). HF is often associated with sodium and water retention, which is thought to be mediated through activation of arginine vasopressin (AVP), neurohormonal activity, the renin-angiotensin-aldosterone system (RAAS), and atrial natriuretic peptide, in order to maintain cardiac output and blood pressure despite decreased left ventricular performance. Angiotensin II (ANG II), in particular, is thought to play a critical role in HF, because of its various effects on vascular tone, kidneys, adrenal glands, brain, heart, and the autonomic nervous system (for review, see Ref. 53). Thus in HF activation of RAAS may become a maladaptive response to arterial underfilling, introducing a vicious cycle leading to increasing morbidity and mortality (17). As a consequence, a variety of pharmaceutical efforts have targeted the RAAS. However, the underlying mechanisms in the impairment of body water and sodium handling...

Congestive heart failure in rats is associated with increased collecting duct vasopressin sensitivity and vasopressin type 2 receptor reexternalization

“…In addition, a recent study by Lütken el at. (20) showed that candesartan treatment reduces the inner medullary AQP2 levels and reduces the apical targeting of APQ2 in CHF rats. Moreover, Wong and Tsui (36) demonstrated normalization of the increased inner medullary AQP2 expression in response to treatment with the angiotensin-converting enzyme (ACE) inhibitor enalapril in cardiomyopathic hamsters (36).…”

AT1 Receptors in the Collecting Duct Directly Modulate the Concentration of Urine

“…10,11 Conversely, pharmacologic blockade of the AT 1 receptor reduces AQP2 expression in experimental heart failure. 9,23 In addition, Li et al 11 have recently shown that angiotensin II stimulates expression and trafficking of AQP2 proteins to the apical surface of immortalized principal cells. Our finding of an impaired response to vasopressin in CD-KOs supports a key interaction between AT 1A receptors in the collecting duct and V2 receptor activation of AQP2.…”

“…10,11,23 To determine whether cellular localization of AQP2 to the apical membrane is altered in the CD-KOs, immunofluorescent labeling of AQP2 was analyzed by confocal microscopy. As shown in Figure 4, under baseline conditions with free access to water, AQP2 immunostaining in the inner medulla showed a weak and diffuse staining pattern that was similar in control ( Figure 4, A and E) and CD-KO ( Figure 4, B and F) mice.…”

Chronic Administration of Oral Vasopressin Type 2 Receptor Antagonist Tolvaptan Exerts Both Myocardial and Renal Protective Effects in Rats With Hypertensive Heart Failure

“…An ACE inhibitor has been also reported to reduce the expressions of V2R and AQP-2 mRNA in the kidney of the cardiomyopathic hamster. 29 Recently, Lütken et al 30 demonstrated that increased expression of AQP2 as well as ENaC and NHE3 in postinfarcted rats with HF were, at least in part, reversed by AT1 receptor antagonism. AVP could potentially stimulate renin secretion directly via activation of V2R or indirectly through reduction of the sodium concentration at the macula densa.…”